T helper 17 cells (Th17) are major contributors to several autoimmune diseases including multiple sclerosis. Interleukin 17 (IL-17) is a proinflammatory cytokine produced by Th17 cells and other immune cells. Although the transcriptional factors involved in Th17 cell differentiation are well understood, less is known about the mechanisms of posttranscriptional gene regulation. The RNA-binding protein human antigen R (HuR) regulates the stability of many target mRNAs via binding the adenylate-uridylate-rich elements (ARE) present in the 3' untranslated region (3'UTR). We previously demonstrated that HuR regulates IL-17 production in Th17 cells. Knockout of HuR in CD4+ T cells reduces IL-17 mRNA half-life, decreases IL-17 production, and inhibits Th17 cell proliferation. Interestingly, Knockout of HuR reduces CCR6 expression on Th17 cells. Furthermore, HuR-/- Th17 cells delay the onset and reduce the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of human multiple sclerosis. Recently, we determined that knockout of HuR inhibits phosphorylation of Stat3 and decreases the expression of Malt1 (mucosa associated lymphoid tissue lymphoma translocation gene 1) and Runx1 in Th17 cells. The central hypothesis is that HuR regulates transcriptional factor activity in Th17 cells for promoting EAE. Specifically, we will first investigate whether HuR enhances Th17 cell differentiation by regulating Malt1 expression. Malt1 is a well-known regulator for NF-B activation in promoting Th17 cell differentiation, and the 3'UTR of Malt1 mRNA contains multiple potential HuR binding-sites by computational analysis. Second, because HuR deficiency decreases the phosphorylation of Stat3, we will determine how HuR promotes Stat3 activation to enhance Th17 cell differentiation. Third, as knockout of HuR reduces the expression of Runx1 in Th17 cells, we will explore the mechanism underlying HuR controlling Runx1 expression to drive Th17 cell differentiation. Furthermore, we will test if HuR stabilizes target mRNAs by preventing microRNAs from binding to same targets in Th17 cells. Finally, we will determine whether overexpression of Malt1 and Runx1 in HuR KO Th17 cells will, at least partially, restore their function for induction of EAE. Collectively, better understanding regulatoy mechanisms of Th17 cell differentiation and functions by HuR is crucial, as targeting HuR may be a novel therapeutic approach for Th17 cell-mediated autoimmune encephalomyelitis.